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References and notes
Vehicle
3 µmol/kg
10 µmol/kg
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Time, min
Figure 3. Effect of bolus i.v. injection of compound 5j on plasma PTH
levels in normal rats.
measurement of the levels of PTH, Ca2+, and compound 5j
in plasma. PTH was measured using specific rat PTH(1-
84) ELISA (Immutopics, San Clemente, CA) and com-
pound 5j was quantified by an LC–MS/MS method.
Plasma levels of compound 5j were maximal at 1 min
after injection and declined rapidly during the next 10–
30 min (Fig. 2). Injection of compound 5j induced a
rapid, but transient dose-related increase in plasma PTH
levels that were maximal at 1 min after the injection.
Plasma PTH levels had returned to pre-dose levels by
10 min (Fig. 3). There were no changes in plasma Ca2+
levels, probably because PTH levels were elevated for
such a short time and/or because the study was only
of 30 min duration. For example, when NPS 2143
(Fig. 1) was infused intravenously, plasma Ca2+ levels
did not start to increase for 60 min.5
In summary, optimization of the substituted 3H-quinaz-
olin-4-ones resulted in the generation of novel potent
calcilytics, which stimulated PTH secretion in vivo.
The series offers a new perspective for the development
of clinically relevant calcium receptor antagonists.